TY - JOUR
T1 - Association and interaction of PPAR-complex gene variants with latent traits of left ventricular diastolic function
AU - Juang, Jyh Ming J.
AU - de las Fuentes, Lisa
AU - Waggoner, Alan D.
AU - Gu, C. Charles
AU - Dávila-Román, Víctor G.
N1 - Funding Information:
The authors would like to acknowledge Joann Reagan, RN, BSN, and Sharon Heuerman, RN, for their assistance with subject recruitment and phenotypic characterization. This research was supported in part by NIH grants R01HL71782 (V.G.D.-R.), R21HL094668, KL2RR024994 and K12RR023249 (L.d.l.F.), AHA0855626G (C.C.G), UL1RR024992 (Clinical and Translational Sciences Award to Washington University), and from the Robert Wood Johnson (L.d.l.F.) and Barnes-Jewish Hospital (V.G.D.-R.) Foundations. Genotyping for PPARGC1A, PPARA, and PPARG was provided, in part, by an award from the SeattleSNPs Program for Genomic Applications (L.d.l.F.).
PY - 2010/4/28
Y1 - 2010/4/28
N2 - Background: Abnormalities in myocardial metabolism and/or regulatory genes have been implicated in left ventricular systolic dysfunction. However, the extent to which these modulate left ventricular diastolic function (LVDF) is uncertain.Methods: Independent component analysis was applied to extract latent LVDF traits from 14 measured echocardiography-derived endophenotypes of LVDF in 403 Caucasians. Genetic association was assessed between measured and latent LVDF traits and 64 single nucleotide polymorphisms (SNPs) in three peroxisome proliferator-activated receptor (PPAR)-complex genes involved in the transcriptional regulation of fatty acid metabolism.Results: By linear regression analysis, 7 SNPs (4 in PPARA, 2 in PPARGC1A, 1 in PPARG) were significantly associated with the latent LVDF trait, whereas a range of 0-4 SNPs were associated with each of the 14 measured echocardiography-derived endophenotypes. Frequency distribution of P values showed a greater proportion of significant associations with the latent LVDF trait than for the measured endophenotypes, suggesting that analyses of the latent trait improved detection of the genetic underpinnings of LVDF. Ridge regression was applied to investigate within-gene and gene-gene interactions. In the within-gene analysis, there were five significant pair-wise interactions in PPARGC1A and none in PPARA or PPARG. In the gene-gene analysis, significant interactions were found between rs4253655 in PPARA and rs1873532 (p = 0.02) and rs7672915 (p = 0.02), both in PPARGC1A, and between rs1151996 in PPARG and rs4697046 in PPARGC1A (p = 0.01).Conclusions: Myocardial metabolism PPAR-complex genes, including within and between genes interactions, may play an important role modulating left ventricular diastolic function.
AB - Background: Abnormalities in myocardial metabolism and/or regulatory genes have been implicated in left ventricular systolic dysfunction. However, the extent to which these modulate left ventricular diastolic function (LVDF) is uncertain.Methods: Independent component analysis was applied to extract latent LVDF traits from 14 measured echocardiography-derived endophenotypes of LVDF in 403 Caucasians. Genetic association was assessed between measured and latent LVDF traits and 64 single nucleotide polymorphisms (SNPs) in three peroxisome proliferator-activated receptor (PPAR)-complex genes involved in the transcriptional regulation of fatty acid metabolism.Results: By linear regression analysis, 7 SNPs (4 in PPARA, 2 in PPARGC1A, 1 in PPARG) were significantly associated with the latent LVDF trait, whereas a range of 0-4 SNPs were associated with each of the 14 measured echocardiography-derived endophenotypes. Frequency distribution of P values showed a greater proportion of significant associations with the latent LVDF trait than for the measured endophenotypes, suggesting that analyses of the latent trait improved detection of the genetic underpinnings of LVDF. Ridge regression was applied to investigate within-gene and gene-gene interactions. In the within-gene analysis, there were five significant pair-wise interactions in PPARGC1A and none in PPARA or PPARG. In the gene-gene analysis, significant interactions were found between rs4253655 in PPARA and rs1873532 (p = 0.02) and rs7672915 (p = 0.02), both in PPARGC1A, and between rs1151996 in PPARG and rs4697046 in PPARGC1A (p = 0.01).Conclusions: Myocardial metabolism PPAR-complex genes, including within and between genes interactions, may play an important role modulating left ventricular diastolic function.
UR - http://www.scopus.com/inward/record.url?scp=77951563206&partnerID=8YFLogxK
U2 - 10.1186/1471-2350-11-65
DO - 10.1186/1471-2350-11-65
M3 - Article
C2 - 20426853
AN - SCOPUS:77951563206
SN - 1471-2350
VL - 11
JO - BMC Medical Genetics
JF - BMC Medical Genetics
IS - 1
M1 - 65
ER -